PROJECT SUMMARY Post-traumatic joint contracture (PTJC) often leads to debilitating impairment following injury, especially in the elbow where even minor injuries can lead to drastic disability. PTJC is a challenging clinical condition that is difficult to reverse, so preventative treatment strategies are urgently needed. Mechanisms governing successful physical therapy are poorly understood; systematic evaluation is needed to determine the potential of physical rehabilitation. Several drugs have demonstrated anti-fibrotic effects in other systems; focused studies are needed to evaluate if biological therapy using these drugs is able to reduce PTJC. Also, the potential synergistic impact of combined physical/biological therapies is unknown. The objective of this study is to utilize a validated animal model of PTJC to investigate physical and biological strategies to preserve mechanics/function (e.g., range of motion and gait patterns) of the elbow joint following injury. SA1: Determine if physical treatments can prevent PTJC and preserve mechanics/function of injured elbows. We will identify whether active motion is successful in reducing PTJC, and determine which governing principles best preserve joint mechanics. Hypothesis: Low-intensity, long-duration physical therapy will be most effective at preserving joint mechanics and function by reducing excessive ECM deposition and tissue fibrosis, while also limiting potential joint wear from high-intensity therapy. SA2: Determine if biological treatments can prevent PTJC and preserve mechanics/function of injured elbows. We will investigate whether the pleiotropic anti- fibrotic effects of simvastatin and losartan can prevent PTJC and identify which treatment protocol best preserves joint mechanics/function. Hypothesis: Both simvastatin and losartan will reduce PTJC severity but a combination of low doses of both drugs will be most effective in preserving joint mechanics and function by reducing the fibrotic response in joint tissues, especially by limiting post-traumatic collagen production. SA3: Determine if synergistic and/or compensatory effects of a combined physical-biological treatment strategy can maintain elbow joint mechanics/function at pre-injury levels. We will investigate the degree to which a well-designed physical therapy protocol (from Aim 1) combined with strategic biological intervention (from Aim 2) can eliminate symptoms of PTJC. Hypothesis: Treatment aimed at both limiting the fibrotic biological response via drug therapy and disrupting fibrosis via physical therapy will be most effective in preserving joint mechanics/function by limiting tissue fibrosis due to synergistic and compensatory benefits of combined therapy. Successful completion of this study will elucidate treatment principles that best prevent contracture and dysfunction after injury via clinically-available physical, biological, and/or combined treatment strategies. Results will be impactful for understanding etiology and pathophysiology in other articulating joints that are susceptible to contracture. This study will leverage an interdisciplinary research team to quantify the mechanical, biological, and functional aspects of PTJC prevention using tools of engineering and biology.